5znc

Plasmodium falciparum purine nucleoside phosphorylase in complex with quinine

spinqualitylabelsall models 5znc, resolution 1.66Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5znc is a 1 chain structure with sequence from Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.66Å Ligands: PO4, QI9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PNPH_PLAFA As part of the purine salvage pathway, catalyzes the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate (PubMed:11707439, PubMed:30602534). Preferentially acts on inosine and guanosine, and to a lesser extent on 2'-deoxyinosine and 2'-deoxyguanosine (PubMed:11707439). Also catalyzes the phosphorylation of S-methyl-5'-thioinosine (MTI) to hypoxanthine; MTI is produced by adenosine deaminase (ADA)-mediated breakdown of S-methyl-5'-thioadenosine (MTA), a major by-product of polyamine biosynthesis (By similarity). Generates hypoxanthine from both the purine salvage pathway and from polyamine metabolism which is required for nucleic acids synthesis (By similarity). Has no activity towards adenosine (PubMed:11707439).[UniProtKB:Q8I3X4] Publication Abstract from PubMed Mechanisms of action (MoAs) have been elusive for most antimalarial drugs in clinical use. Decreasing responsiveness to antimalarial treatments stresses the need for a better resolved understanding of their MoAs and associated resistance mechanisms. In the present work, we implemented the cellular thermal shift assay coupled with mass spectrometry (MS-CETSA) for drug target identification in Plasmodium falciparum, the main causative agent of human malaria. We validated the efficacy of this approach for pyrimethamine, a folic acid antagonist, and E64d, a broad-spectrum cysteine proteinase inhibitor. Subsequently, we applied MS-CETSA to quinine and mefloquine, two important antimalarial drugs with poorly characterized MoAs. Combining studies in the P. falciparum parasite lysate and intact infected red blood cells, we found P. falciparum purine nucleoside phosphorylase (PfPNP) as a common binding target for these two quinoline drugs. Biophysical and structural studies with a recombinant protein further established that both compounds bind within the enzyme's active site. Quinine binds to PfPNP at low nanomolar affinity, suggesting a substantial contribution to its therapeutic effect. Overall, we demonstrated that implementation of MS-CETSA for P. falciparum constitutes a promising strategy to elucidate the MoAs of existing and candidate antimalarial drugs. Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay.,Dziekan JM, Yu H, Chen D, Dai L, Wirjanata G, Larsson A, Prabhu N, Sobota RM, Bozdech Z, Nordlund P Sci Transl Med. 2019 Jan 2;11(473). pii: 11/473/eaau3174. doi:, 10.1126/scitranslmed.aau3174. PMID:30602534 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Purine nucleoside phosphorylase 3D structures

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